tbuckley/cabot-search huggingface dataset:
RNA editing: Expanding the potential of RNA therapeutics
Authors: Brian J. Booth, Sami Nourreddine, Dhruva Katrekar, Yiannis Savva, Debojit Bose, Thomas J. Long, David J. Huss, Prashant Mali
Journal: Molecular Therapy (2023)

RNA therapeutics have had a tremendous impact on medicine, recently exemplified by the rapid development and deployment of mRNA vaccines to combat the COVID-19 pandemic. In addition, RNA-targeting drugs have been developed for diseases with significant unmet medical needs through selective mRNA knockdown or modulation of pre-mRNA splicing. Recently, RNA editing, particularly antisense RNA-guided adenosine deaminase acting on RNA (ADAR)-based programmable A-to-I editing, has emerged as a powerful tool to manipulate RNA to enable correction of disease-causing mutations and modulate gene expression and protein function. Beyond correcting pathogenic mutations, the technology is particularly well suited for therapeutic applications that require a transient pharmacodynamic effect, such as the treatment of acute pain, obesity, viral infection, and inflammation, where it would be undesirable to introduce permanent alterations to the genome. Furthermore, transient modulation of protein function, such as altering the active sites of enzymes or the interface of protein-protein interactions, opens the door to therapeutic avenues ranging from regenerative medicine to oncology. These emerging RNA-editing-based toolsets are poised to broadly impact biotechnology and therapeutic applications. Here, we review the emerging field of therapeutic RNA editing, highlight recent laboratory advancements, and discuss the key challenges on the path to clinical development. RNA therapeutics have had a tremendous impact on medicine, recently exemplified by the rapid development and deployment of mRNA vaccines to combat the COVID-19 pandemic. In addition, RNA-targeting drugs have been developed for diseases with significant unmet medical needs through selective mRNA knockdown or modulation of pre-mRNA splicing. Recently, RNA editing, particularly antisense RNA-guided adenosine deaminase acting on RNA (ADAR)-based programmable A-to-I editing, has emerged as a powerful tool to manipulate RNA to enable correction of disease-causing mutations and modulate gene expression and protein function. Beyond correcting pathogenic mutations, the technology is particularly well suited for therapeutic applications that require a transient pharmacodynamic effect, such as the treatment of acute pain, obesity, viral infection, and inflammation, where it would be undesirable to introduce permanent alterations to the genome. Furthermore, transient modulation of protein function, such as altering the active sites of enzymes or the interface of protein-protein interactions, opens the door to therapeutic avenues ranging from regenerative medicine to oncology. These emerging RNA-editing-based toolsets are poised to broadly impact biotechnology and therapeutic applications. Here, we review the emerging field of therapeutic RNA editing, highlight recent laboratory advancements, and discuss the key challenges on the path to clinical development.
Berotralstat for the prophylaxis of hereditary angioedema—Real‐world evidence data from the United Kingdom
Authors: Manisha Ahuja, Anthony Dorr, Eniola Bode, Anne P. R. Boulton, Matthew Buckland, Samuel Chee, Claire Dalley, Sarah Denman, Anjali Ekbote, Shuayb Elkhalifa, Tariq El‐Shanawany, Efrem Eren, Archana Herwadkar, Tomaz Garcez, Harichandana Ghanta, Alexandros Grammatikos, Sofia Grigoriadou, Rashmi Jain, Lorena Lorenzo, Ania Manson, Emily Moon, Sai Murng, Aveen Murphy, Leman Mutlu, Nicholas Peters, Kavitha Sooriyakumar, Catherine Stroud, Katie Townsend, Robert L. Yellon, Patrick Yong, Sorena Kiani‐Alikhan
Journal: Allergy (2023)

AppendixS1 AppendixS2 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Acidity‐Biodegradable Iridium‐Coordinated Nanosheets for Amplified Ferroptotic Cell Death Through Multiple Regulatory Pathways
Authors: Lili Huang, Tongtong Nie, Lixian Jiang, Ying Chen, Yixuan Zhou, Xiaojun Cai, Yuanyi Zheng, Longchen Wang, Jianrong Wu, Tao Ying
Journal: Advanced Healthcare Materials (2023)

Abstract Ferroptosis‐based treatment strategies display the potential to suppress some malignant tumors with intrinsic apoptosis resistance. However, current related cancer treatments are still hampered by insufficient intracellular reactive oxygen species (ROS) levels and Fe 2+ contents, posing considerable challenges for their clinical translation. Herein, an intracellular acid‐biodegradable iridium‐coordinated nanosheets (Ir‐Hemin) with sonodynamic therapy (SDT) properties to effectively induce ferroptosis in tumor cells through multiple regulatory pathways are proposed. Under ultrasound (US) irradiation, Ir‐Hemin nanosheets act as nanosonosensitizers to effectively generate ROS, subsequently causing the accumulation of lipid peroxides (LPO) and inducing ferroptotic cell death. Furthermore, these Ir‐Hemin nanosheets decompose quickly to release hemin and Ir(IV), which deplete intracellular glutathione (GSH) to deactivate the enzyme glutathione peroxidase 4 (GPX4) and initiate the ferroptosis pathway. Specifically, the released hemin enables heme oxygenase 1 (HO‐1) upregulation for endogenous ferrous ion supplementation, which compensates for the toxicity concerns brought about by the large uptake of exogenous iron. Surprisingly, Ir‐Hemin nanosheets exhibit high tumor accumulation and trigger effective ferroptosis for tumor therapy. These Ir‐Hemin nanosheets display pronounced synergistic anticancer efficacy under US stimulation both in vitro and in vivo, providing a strong rationale for the application of ferroptosis in cancer treatment.
A polygenic two-hit hypothesis for prostate cancer
Authors: Kathleen E Houlahan, Julie Livingstone, Natalie S Fox, Natalie Kurganovs, Helen Zhu, Jocelyn Sietsma Penington, Chol-Hee Jung, Takafumi N Yamaguchi, Lawrence E Heisler, Richard Jovelin, Anthony J Costello, Bernard J Pope, Amar U Kishan, Niall M Corcoran, Robert G Bristow, Sebastian M Waszak, Joachim Weischenfeldt, Housheng H He, Rayjean J Hung, Christopher M Hovens, Paul C Boutros
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Prostate cancer is one of the most heritable cancers. Hundreds of germline polymorphisms have been linked to prostate cancer diagnosis and prognosis. Polygenic risk scores can predict genetic risk of a prostate cancer diagnosis. Although these scores inform the probability of developing a tumor, it remains unknown how germline risk influences the tumor molecular evolution. We cultivated a cohort of 1250 localized European-descent patients with germline and somatic DNA profiling. Men of European descent with higher genetic risk were diagnosed earlier and had less genomic instability and fewer driver genes mutated. Higher genetic risk was associated with better outcome. These data imply a polygenic “two-hit” model where germline risk reduces the number of somatic alterations required for tumorigenesis. These findings support further clinical studies of polygenic risk scores as inexpensive and minimally invasive adjuncts to standard risk stratification. Further studies are required to interrogate generalizability to more ancestrally and clinically diverse populations.
Insights into atopic dermatitis pathogenesis lead to newly approved systemic therapies
Authors: Anna M Trier, Brian S Kim
Journal: British Journal of Dermatology (2022)

Abstract Atopic dermatitis (AD) is a common inflammatory skin disease characterized by scaly, oozing skin and itch. In moderate-to-severe AD, treatment options have been historically very limited and off-label use has been a common method for disease management. For decades, ciclosporin A was the only systemic immunosuppressive drug approved in most European countries to address this major unmet medical need. However, increased understanding of the pathophysiology of AD has led to a revolution in the treatment of this potentially debilitating disease. Following the approval of the first biological therapy for AD in 2017, there has been a rapid expansion of compounds under development and four additional systemic therapies have been approved in Europe and the USA within the past 3 years alone. In this review, we underscore how key breakthroughs have transformed the therapeutic landscape of AD, leading to a major expansion of type 2 immunity-targeted biological therapies, exploration of neuroimmune modulatory agents, and interest in Janus kinase inhibition.
Validation of novel diagnostic criteria for atopic dermatitis in an adult and elderly Chinese population
Authors: Yik Weng Yew, Christian J Apfelbacher
Journal: British Journal of Dermatology (2023)

This is an invited commentary on the article titled “Validation of the main diagnostic criteria of atopic dermatitis and proposing a novel diagnostic criteria in adult and elderly Chinese populations: a multicenter, prospective, clinical setting-based study.”
Temporal trends in the incidence of malignant and nonmalignant primary brain and central nervous system tumors by the method of diagnosis in England, 1993–2017
Authors: Usama M Ali, Diana R Withrow, Andrew D Judge, Puneet Plaha, Sarah C Darby
Journal: Neuro-Oncology (2023)

Abstract Background Several studies report increases in the incidences of primary central nervous system (CNS) tumors. The reasons for this are unclear. Methods Data on all 188 340 individuals diagnosed with a primary CNS tumor in England (1993–2017) were obtained from the National Cancer Registration and Analysis Service. Data on all computerized tomography (CT) head and magnetic resonance imaging (MRI) brain scans in England (2013–2017) were obtained from the National Health Service Digital. Age-sex-standardized annual incidence rates per 100 000 population (ASR) were calculated by calendar year, tumor behavior, tumor location, and method of diagnosis. Temporal trends were quantified using average annual percent change (AAPC). Results The ASR for all CNS tumors increased from 13.0 in 1993 to 18.6 in 2017 (AAPC: +1.5%, 95% CI: 1.3, 1.7). The ASR for malignant tumors (52% overall) remained stable (AAPC: +0.5%, 95% CI: −0.2, 1.3), while benign tumors (37% overall) increased (AAPC: +2.6%, 95% CI: 1.2, 4.0). Among the 66% of benign tumors that were microscopically confirmed, the ASR increased modestly (AAPC: +1.3%, 95% CI: 0.5, 2.1). However, among the 25% of benign tumors that were radiographically confirmed, the ASR increased substantially (AAPC: 10.2%, 95% CI: 7.9, 12.5), principally driven by large increases in those who are aged 65+ years. The rate of CT head scans in Accident &amp; Emergency (A&amp;E) increased during 2013–2017, with especially large increases in 65–84 and 85+-year-olds (AAPCs: +18.4% and +22.5%). Conclusions Increases in CNS tumor incidence in England are largely attributable to the greater detection of benign tumors. This could be the result of the increasing use of neuroimaging, particularly CT head scans in A&amp;E in people who are aged 65+ years.
Reconstruction of Plastid Proteomes of Apicomplexans and Close Relatives Reveals the Major Evolutionary Outcomes of Cryptic Plastids
Authors: Varsha Mathur, Eric D Salomaki, Kevin C Wakeman, Ina Na, Waldan K Kwong, Martin Kolisko, Patrick J Keeling
Journal: Molecular Biology and Evolution (2023)

Abstract Apicomplexans and related lineages comprise many obligate symbionts of animals; some of which cause notorious diseases such as malaria. They evolved from photosynthetic ancestors and transitioned into a symbiotic lifestyle several times, giving rise to species with diverse non-photosynthetic plastids. Here, we sought to reconstruct the evolution of the cryptic plastids in the apicomplexans, chrompodellids, and squirmids (ACS clade) by generating five new single-cell transcriptomes from understudied gregarine lineages, constructing a robust phylogenomic tree incorporating all ACS clade sequencing datasets available, and using these to examine in detail, the evolutionary distribution of all 162 proteins recently shown to be in the apicoplast by spatial proteomics in Toxoplasma. This expanded homology-based reconstruction of plastid proteins found in the ACS clade confirms earlier work showing convergence in the overall metabolic pathways retained once photosynthesis is lost, but also reveals differences in the degrees of plastid reduction in specific lineages. We show that the loss of the plastid genome is common and unexpectedly find many lineage- and species-specific plastid proteins, suggesting the presence of evolutionary innovations and neofunctionalizations that may confer new functional and metabolic capabilities that are yet to be discovered in these enigmatic organelles.
Severe tracheal involvement in type XVII collagen junctional epidermolysis bullosa
Authors: Alizée Bozonnat, Laura Polivka, Stéphanie Leclerc-Mercier, Romain Luscan, Fabienne Charbit-Henrion, Christine Bodemer, Alexandre Lapillonne, Smail Hadj-Rabia
Journal: British Journal of Dermatology (2023)

In COLXVII-junctional epidermolysis bullosa, mucosal involvement remains inconsistent and is limited to the oral cavity and the oesophagus. We documented the observation of a patient presenting with tracheal damage.
Forthcoming Meetings
Journal: Neuro-Oncology (2023)

Journal Article Forthcoming Meetings Get access Neuro-Oncology, Volume 25, Issue 1, January 2023, Page 217, https://doi.org/10.1093/neuonc/noac259 Published: 05 January 2023 Article history Corrected and typeset: 05 January 2023 Published: 05 January 2023
Antibodies to varicella-zoster virus and three other herpesviruses and survival in adults with glioma
Authors: Geno Guerra, Lucie McCoy, Helen M Hansen, Terri Rice, Annette M Molinaro, Joseph L Wiemels, John K Wiencke, Margaret Wrensch, Stephen S Francis
Journal: Neuro-Oncology (2023)

Abstract Background Lifetime exposure to the varicella-zoster virus (VZV) has been consistently inversely associated with glioma risk, however, the relationship of VZV with survival in adults with glioma has not been investigated. In this study, we analyzed the survival of adults with glioma in relation to their antibody measurements to 4 common herpes viral infections, including VZV, measured post-diagnosis. Methods We analyzed IgG antibody measurements to VZV, cytomegalovirus (CMV), herpes simplex virus 1/2 (HSV), and Epstein-Barr virus (EBV) collected from 1378 adults with glioma diagnosed between 1991 and 2010. Blood was obtained a median of 3 months after surgery. Associations of patient IgG levels with overall survival were estimated using Cox models adjusted for age, sex, self-reported race, surgery type, dexamethasone usage at blood draw, and tumor grade. Models were stratified by recruitment series and meta-analyzed to account for time-dependent treatment effects. Results VZV antibody seropositivity was associated with improved survival outcomes in adults with glioma (Hazard ratio, HR = 0.70, 95% Confidence Interval 0.54–0.90, P = .006). Amongst cases who were seropositive for VZV antibodies, survival was significantly improved for those above the 25th percentile of continuous reactivity measurements versus those below (HR = 0.76, 0.66–0.88, P = .0003). Antibody seropositivity to EBV was separately associated with improved survival (HR = 0.71, 0.53–0.96, P = .028). Antibody positivity to 2 other common viruses (CMV, HSV) was not associated with altered survival. Conclusions Low levels of VZV or EBV antibodies are associated with poorer survival outcomes for adults with glioma. Differential immune response rather than viral exposure may explain these findings.
Metformin coordinates with mesenchymal cells to promote VEGF-mediated angiogenesis in diabetic wound healing through Akt/mTOR activation
Authors: Fangzhou Du, Mengmeng Liu, Jingwen Wang, Lvzhong Hu, Dongao Zeng, Shaocong Zhou, Lixing Zhang, Meijia Wang, Xi Xu, Chenglong Li, Jingzhong Zhang, Shuang Yu
Journal: Metabolism (2023)
Advances in palliative care in neuro-oncology come in many forms
Authors: Eli L Diamond
Journal: Neuro-Oncology (2023)

Journal Article Advances in palliative care in neuro-oncology come in many forms Get access Eli L Diamond Eli L Diamond Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York, USA Corresponding Author: Eli L. Diamond, MD, Memorial Sloan Kettering Cancer Center, 160 East 53rd St., Second Floor Neurology, New York, NY 10022 (diamone1@mskcc.org). https://orcid.org/0000-0001-5456-5961 Search for other works by this author on: Oxford Academic PubMed Google Scholar Neuro-Oncology, Volume 25, Issue 3, March 2023, Pages 457–458, https://doi.org/10.1093/neuonc/noac287 Published: 04 January 2023 Article history Published: 04 January 2023 Corrected and typeset: 18 February 2023
Detection of extensive host–virus DNA hybrids in human polyomavirus 7-associated pruritic rash
Authors: Gabriel J Starrett, Jae W Lee, Subhajit Chatterjee, Jaroslaw J Jedrych
Journal: British Journal of Dermatology (2023)

Human polyomavirus 7 (HPyV7) is associated with pruritic dermatoses that primarily affect immunocompromised patients. We identified extensive host–virus DNA hybrids in HPyV7-associated rash, highlighting the need for additional studies on long-term consequences of HPyV7 infection, including its oncogenic potential.
Rituximab and risk of infections in patients with pemphigus: answers from a global population-based cohort study
Authors: Simone Cazzaniga, Luigi Naldi, Luca Borradori
Journal: British Journal of Dermatology (2023)

Journal Article Rituximab and risk of infections in patients with pemphigus: answers from a global population-based cohort study Get access Simone Cazzaniga, Simone Cazzaniga Department of Dermatology, Inselspital University Hospital of Bern, Bern, SwitzerlandCentro Studi GISED, Bergamo, Italy Correspondence: Simone Cazzaniga. Email: simone.cazzaniga@gised.it https://orcid.org/0000-0001-8161-6138 Search for other works by this author on: Oxford Academic Google Scholar Luigi Naldi, Luigi Naldi Centro Studi GISED, Bergamo, ItalyDivision of Dermatology, San Bortolo Hospital, Vicenza, Italy https://orcid.org/0000-0002-3160-2835 Search for other works by this author on: Oxford Academic Google Scholar Luca Borradori Luca Borradori Department of Dermatology, Inselspital University Hospital of Bern, Bern, Switzerland https://orcid.org/0000-0003-0424-6297 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 188, Issue 4, April 2023, Pages 454–455, https://doi.org/10.1093/bjd/ljad005 Published: 06 January 2023 Article history Received: 02 January 2023 Published: 06 January 2023 Accepted: 16 January 2023 Corrected and typeset: 31 January 2023
Epithelial-intrinsic defects in TGFβR signaling drive local allergic inflammation manifesting as eosinophilic esophagitis
Authors: Karen Laky, Jessica L. Kinard, Jenny Min Li, Ian N. Moore, Justin Lack, Elizabeth R. Fischer, Juraj Kabat, Rachel Latanich, Nicholas C. Zachos, Ajinkya R. Limkar, Katherine A. Weissler, Robert W. Thompson, Thomas A. Wynn, Harry C. Dietz, Anthony L. Guerrerio, Pamela A. Frischmeyer-Guerrerio
Journal: Science Immunology (2023)

Allergic diseases are a global health challenge. Individuals harboring loss-of-function variants in transforming growth factor–β receptor (TGFβR) genes have an increased prevalence of allergic disorders, including eosinophilic esophagitis. Allergic diseases typically localize to mucosal barriers, implicating epithelial dysfunction as a cardinal feature of allergic disease. Here, we describe an essential role for TGFβ in the control of tissue-specific immune homeostasis that provides mechanistic insight into these clinical associations. Mice expressing a TGFβR1 loss-of-function variant identified in atopic patients spontaneously develop disease that clinically, immunologically, histologically, and transcriptionally recapitulates eosinophilic esophagitis. In vivo and in vitro, TGFβR1 variant–expressing epithelial cells are hyperproliferative, fail to differentiate properly, and overexpress innate proinflammatory mediators, which persist in the absence of lymphocytes or external allergens. Together, our results support the concept that TGFβ plays a fundamental, nonredundant, epithelial cell–intrinsic role in controlling tissue-specific allergic inflammation that is independent of its role in adaptive immunity.
Nanoscale coordination polymers enabling antioxidants inhibition for enhanced chemodynamic therapy
Authors: Yan Zhang, Faming Wang, Lai Shi, Mengrou Lu, Keng-Jung Lee, Mackenzie Maurer Ditty, Yunhui Xing, Hong-Zhang He, Xi Ren, Si-Yang Zheng
Journal: Journal of Controlled Release (2023)

Reactive oxygen species (ROS) generation to induce cell death is an effective strategy for cancer therapy. In particular, chemodynamic therapy (CDT), using Fenton-type reactions to generate highly cytotoxic hydroxyl radical (•OH), is a promising treatment modality. However, the therapeutic efficacy of ROS-based cancer treatment is still limited by some critical challenges, such as overexpression of enzymatic and non-enzymatic antioxidants by tumor cells, as well as the low tumor targeting efficiency of therapeutic agents. To address those problems, biomimetic CuZn protoporphyrin IX nanoscale coordination polymers have been developed, which significantly amplify oxidative stress against tumors by simultaneously inhibiting enzymatic and non-enzymatic antioxidants and initiating the CDT. In this design, cancer cell membrane camouflaged nanoparticle exhibits an excellent homotypic targeting effect. After being endocytosed into tumor cells, the nanoparticles induce depletion of the main non-enzymatic antioxidant glutathione (GSH) by undergoing a redox reaction with GSH. Afterward, the redox reaction generated cuprous ion (Cu+) works as a CDT agent for •OH generation. Furthermore, the released Zn protoporphyrin IX strongly inhibits the activity of the typical enzymatic antioxidant heme oxygenase-1. This tetra-modal synergistic strategy endows the biomimetic nanoparticles with great capability for anticancer therapy, which has been demonstrated in both in vitro and in vivo studies.
Silent recognition of flagellins from human gut commensal bacteria by Toll-like receptor 5
Authors: Sara J. Clasen, Michael E. W. Bell, Andrea Borbón, Du-Hwa Lee, Zachariah M. Henseler, Jacobo de la Cuesta-Zuluaga, Katarzyna Parys, Jun Zou, Yanling Wang, Veronika Altmannova, Nicholas D. Youngblut, John R. Weir, Andrew T. Gewirtz, Youssef Belkhadir, Ruth E. Ley
Journal: Science Immunology (2023)

Flagellin, the protein subunit of the bacterial flagellum, stimulates the innate immune receptor Toll-like receptor 5 (TLR5) after pattern recognition or evades TLR5 through lack of recognition. This binary response fails to explain the weak agonism of flagellins from commensal bacteria, raising the question of how TLR5 response is tuned. Here, we screened abundant flagellins present in metagenomes from human gut for both TLR5 recognition and activation and uncovered a class of flagellin-TLR5 interaction termed silent recognition. Silent flagellins were weak TLR5 agonists despite pattern recognition. Receptor activity was tuned by a TLR5-flagellin interaction distal to the site of pattern recognition that was present in Salmonella flagellin but absent in silent flagellins. This interaction enabled flagellin binding to preformed TLR5 dimers and increased TLR5 signaling by several orders of magnitude. Silent recognition by TLR5 occurred in human organoids and mice, and silent flagellin proteins were present in human stool. These flagellins were produced primarily by the abundant gut bacteria Lachnospiraceae and were enriched in nonindustrialized populations. Our findings provide a mechanism for the innate immune system to tolerate commensal-derived flagellins while remaining vigilant to the presence of flagellins produced by pathogens.